Arterial remodeling is a major pathophysiological mechanism underlying clinical cardiovascular disorders such as hypertension, atherosclerosis and restenosis. We examined heparan sulfate proteoglycan homeostasis as a mechanism of regulation of arterial vascular remodeling in response to altered mechanical environments such as hypertension and injury. We first studied the effect of in-vitro mechanical strain on the ability of endothelial cells to inhibit vascular smooth muscle cell proliferation. Under these conditions we found mechanical strain increased endothelial inhibition of smooth muscle cell proliferation through increased production of heparan sulfate proteoglycans. Using inhibitors to p38 MAPK and ERK, we showed that activation of both of these pathways was essential for load-induced heparan sulfate production, TGF-,f1 activation, smad-2 activation and increased FGF-2 uptake. Further, we exposed cells to strain in the presence of a neutralizing antibody to TGF-P 1 and demonstrated that autocrine TGF-1l signaling was essential for load-induced HSPG production and sustained p38 MAPK and ERK activation.

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(cont.) We also examined the endothelium of spontaneously hypertensive rats using immunohistochemical staining for heparan sulfate proteoglycan core proteins, TGF-31 and phosphorylated signaling intermediates and found results that correlated well with our in-vitro experiments. Taken together these results imply a novel paradigm of vascular remodeling to mechanical stimuli in which net arterial remodeling is controlled by the dynamic interplay between pro-growth signals from vascular smooth muscle cells and anti-growth signals from endothelial cells. In a second portion of this work, we examined the role of heparanase in vascular remodeling. Using siRNA gene silencing and overexpression techniques, we showed that alterations in heparanase expression lead to a profound modulation in endothelial inhibition of vascular smooth muscle cell proliferation. In vivo, we quantified heparanase expression in animal models of hypertension, vascular disease and injury. Immunohistochemical analysis of the aortae of hypertensive rats revealed an increase in endothelial production of heparanase that strongly correlated with increased aortic structural remodeling.

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(cont.) Studies of vascular injury with stenting in the Zucker rat model of diabetes showed a relationship between neointimal heparanase expression and lesion thickness. Our results define a new role for heparanase as a key molecular controller of vascular remodeling in diverse disease states.

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by Aaron B. Blair.

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148 leaves

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eng

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Massachusetts Institute of Technology

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M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

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http://dspace.mit.edu/handle/1721.1/7582

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Harvard University--MIT Division of Health Sciences and Technology.

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The role of heparan sulfate proteoglycans and heparanase in the control of vascular remodeling